Readthrough compounds for nonsense mutations: bridging the translational gap
Spelier, Sacha; van Doorn, Eveline P.M.; van der Ent, Cornelis K.; Beekman, Jeffrey M.; Koppens, Martijn A.J.
(2023) Trends in molecular medicine, volume 29, issue 4, pp. 297 - 314
(Article)
Abstract
Approximately 10% of all pathological mutations are nonsense mutations that are responsible for several severe genetic diseases for which no treatment regimens are currently available. The most widespread strategy for treating nonsense mutations is by enhancing ribosomal readthrough of premature termination codons (PTCs) to restore the production of the full-length
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protein. In the past decade several compounds with readthrough potential have been identified. However, although preclinical results on these compounds are promising, clinical studies have not yielded positive outcomes. We review preclinical and clinical research related to readthrough compounds and characterize factors that contribute to the observed translational gap.
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Keywords: nonsense mutations, nonsense-mediated decay, rare diseases, readthrough, translational gap, Molecular Medicine, Molecular Biology
ISSN: 1471-4914
Publisher: Elsevier Limited
Note: Funding Information: J.M.B. reports personal fees from Vertex Pharmaceuticals, Proteostasis Therapeutics, Eloxx Pharmaceuticals, Teva Pharmaceutical Industries, and Galapagos, outside the submitted work. In addition, J.M.B. has a patent related to the FIS assay with royalties paid. C.K.v.d.E. reports grants from GSK, Nutricia, TEVA, Gilead, Vertex, ProQR, Proteostasis, Galapagos NV, and Eloxx outside the submitted work. In addition, C.K.v.d.E. has a patent 10006904 with royalties paid. The other authors declare no conflicts of interest. Funding Information: This study was supported by the Nederlandse Cystic Fibrosis Stichting (NCFS) HIT-CF3 program and Elisabeth von Freyburg Stichting . We thank Dr Saskia Houwen (rehabilitation physician, Radboud University Medical Center) and Dr Friso Langen (Fletiopharma consultant) for sharing their knowledge and experience in the context of DMD. All illustrations were created with BioRender.com . Publisher Copyright: © 2023 The Authors
(Peer reviewed)